The invention relates to novel carbonylated (aza)cyclohexane derivatives that potently bind to the dopamine D3 receptor as partial, full or inverse agonists and antagonists. This receptor, a D2-like receptor, is discretely expressed in only but a few brain projections areas of dopamine neurons, within dopamine neurons themselves (auto-receptors) and in discrete peripheral organs, e.g. the kidney (Schwartz et al. Clinical NeuroPharmacol, 1993, 16, 295). It has been suggested, or even demonstrated that such brain localisations imply a role of this receptor subtype in a number of physiological or pathological processes such as cognition, dementia, psychosis, substance abuse and dependence, mood regulation and disorders (e.g. depression or anxiety), motor regulation and disorders (e.g. Parkinson disease, dyskinesias or equilibration disorders).
In addition, peripheral D3 receptors, namely in kidney, seem involved in the control of hormone secretion, diabetic disorders or blood pressure (Jose et al., Curr. Opin. Nephrol. Hypertens., 2002, 11, 87; Gross et al Lab. Invest., 2006, 86, 862). These considerations indicate that modulation (via partial, full or inverse agonism or antagonism) of dopamine D3 receptors represents a potentially novel approach to treating diseases of the central nervous system in neurology and psychiatry as well as diseases of the cardiovascular or hormonal systems.
The international patent application WO 01/49679 discloses arylpiperazine derivatives that display dopamine antagonist properties on its receptors D3 and D4; however, these compounds have a phenyl group on the position 4 of the piperazine substituted by an halogen atom, and, on the other hand, on the position 1 of the piperazine, an alkylene group optionally substituted by a carbonyl group, and then a 5- or 6-membered aza heterocycle fused with a phenyl group, such as indoline or isoquinoleine.
The international patent application PCT/FR05/02964 discloses arylpiperazine derivatives having an alkylene group and an indoline cycle. These compounds are selective ligands of D3 receptor.
Unexpectedly, it has now been discovered that the compounds according to the invention, which represent a new family of arylpiperazine derivatives, display a high affinity for the D3 receptor of dopamine. By contrast to the compounds disclosed in WO 01/49769 and in PCT/FR05/02964, the compounds according to the invention have an aza heterocycle, such as an arylpiperazine, and an alkylene group substituted by an (aza)cyclohexyl group. Further, they are selective ligands of D3 receptor.
These compounds are useful as medicaments, notably in neurology and psychiatry, particularly in Parkinson's disease, schizophrenia, dementia, depression, mania, anxiety, dyskinesias, equilibration disorders, Gilles de la Tourette's disease. Further, these compounds are useful for treating drug and tobacco dependency.
They are also useful for preventing or treating cardiovascular disorders implying the peripheral dopamine receptors, particularly in kidneys, such as hypertension, cardiac failure, and other disorders such as renal insufficiency or diabetes.
These compounds are also useful for preventing or treating hormonal disorders implying dopamine receptors in the hypothalalamus pituitary complex, such as menopausal disorders or growth disorders.
According to a first object, the present invention concerns new compounds of formula (I):

with NR1R2 chosen from the group selected within:

Z chosen from the group selected within:

R representing alkyl; cyanoalkyl monohalogenocyanoalkyl; polyhalogenocyanoalkyl; hydroxyalkyl monohalogenoalkyl; polyhalogenoalkyl; cycloalkyl; monhalogenocycloalkyl; polyhalogenocycloalkyl; cyanocycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; monohalogeno-alkoxyalkyl polyhalogenoalkoxyalkyl; alkoxyalkoxyalkyl monohalogeno-alkoxyalkoxyalkyl; polyhalogenoalkoxyalkoxyalkyl; alkylcarbonyl aryl; mono- or polyhalogenoaryl; aryloxy; aryloxyalkyl; mono- or polyhalogenoaryloxyalkyl; arylalkoxy; alkenyl cycloalkenyl; cycloalkenylalkyl; cyclalkenyl fused with benzene; alkynyl, amino; alkylamino; dialkylamino; dialkylaminoalkyl; monohalogenoalkylamino; monohalogenodialkylamino; halodialkylaminoalkyl; polyhalogenoalkylamino; polyhalogenodialkylamino; polyhalogenodialkylaminoalkyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl aminocarbonylalkyl; alkylsulfanylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl;
n being an integer from 1 to 3;
m being an integer from 0 to 4;
Ar representing an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
with the proviso that:
when Z is a) NHCH and NR1R2 is 1) with Ar representing a phenyl fused with a carbocycle and R is non aromatic heterocyclyl(CH2)m with m=0, then the heterocycle is linked to the carbonyl by a carbon atom,
when Z is a) NHCH, then R is not alkyl, unsubstituted cycloalkyl, aryl, heteroaryl or heteroarlyalkyl;
when Z is a) NHCH and NR1R2 is 1) with Ar representing a phenyl substituted with two chlorine atoms or fused with a carbocycle, then R is not amino, alkylamino, dialkylamino, monohalogenoalkylamino, monohalogenodialkylamino, polyhalogenoalkylamino, polyhalogenodialkylamino, alkyl, alkenyl, aryl or unsubstituted cycloalkyl;
when Z is a) NHCH and NR1R2 is 1) with Ar representing an unsubstituted phenyl, then R is not alkyl, aryl or unsubstituted cycloalkyl;
when Z is a) NHCH and NR1R2 is 4), then R is not aryl, aralkyl, aralkoxyalkyl, aralkylsulfanylalkyl; and
when Z is b) N, then R is not amino, alkylamino, dialkylamino or halogenoderivative thereof,
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably, NR1R2 is 1):

Preferably, Z is a).

Preferably, R is cyanoalkyl, polyhalogenocyanoalkyl, hydroxyalkyl, polyhalogenoalkyl, cyanocycloalkyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkylcarbonyl, aryloxyalkyl, mono- or polyhalogenoaryloxyalkyl, arylalkoxy, alkenyl, cycloalkenyl, non aromatic heterocyclyl(CH2)m wherein the non aromatic heterocycle is optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen, alkylcarbonylalkyl, acylaminoalkyl, aminocarbonylalkyl, alkylsulfanylalkyl, alkylsulfonylalkyl,
m being an integer from 0 to 4, notably 0 or 2.
Preferably, Ar represents an aryl, more preferably phenyl.
Preferably, Ar is substituted with one or more alkyl, cyano, halogeno, alkoxy, polyhalogenoalkoxy, alcanediyl, dialkylamino, alkylsulfanyl, aryl, aralkyl, aryloxy, alkoxycarbonylamino, acyl, alkylsulfonylamino, polyhalogenoalkyl, hydroxy, hydroxyalkyl, oxoalkyl.
Preferably, Ar is unsubstituted or substituted with one or more alkyl, polyhalogenoalkyl, halogen or cyano, more preferably with alkyl or polyhalogenoalkyl.
The present invention encompasses the following embodiments:                NR1R2 is a group of formula 1) and Z is a group a);        NR1R2 is a group of formula 1) and Z is a group b), c) or d), more preferably those where NR1R2 is 1) and Z is c);        NR1R2 is a group of formula 1) and Z is a group e) or f);        NR1R2 is a group of formula 2) or 3), more preferably those where NR1R2 is 2) and Z is a), those where NR1R2 is 2) and Z is c) and those where NR1R2 is 3) and Z is c);        NR1R2 is a group of formula 4) and Z is a group a);        NR1R2 is a group of formula 4) and Z is a group b), c) or d), more preferably where NR1R2 is 4) and Z is c);        NR1R2 is a group of formula 4) and Z is a group e) or f)        
wherein R, Ar, m, n are defined as above.
Preferably, the compounds of the invention are those of formula (A):
where:
R is chosen from cyanoalkyl; monohalogenoalkyl; polyhalogenoalkyl; monohalogenocycloalkyl; polyhalogeno-cycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; monohalogenoalkoxyalkyl; polyhalogenoalkoxyalkyl; alkoxyalkoxyalkyl; monohalogenoalkoxyalkoxyalkyl; polyhalogenoalkoxyalkoxyalkyl; monohalogenocyanoalkyl; polyhalogenocyanoalkyl; cyanocycloalkyl; aryloxy; aryloxyalkyl; arylalkoxy; cycloalkenyl; cycloalkenylalkyl; cycloalkenyl fused with benzene; alkynyl; dialkylaminoalkyl; hydroxyalkyl; polyhalogenodialkylaminoalkyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl; aminocarbonylalkyl; alkylsulfanylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl; alkylcarbonyl; mono- or polyhalogenoaryl; mono- or polyhalogenoaryloxyalkyl;
m being an integer from 0 to 4,
Ar represents an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably, in formula (A):
R is chosen from cyanoalkyl; polyhalogenoalkyl; alkoxy; alkoxyalkyl; polyhalogenocyanoalkyl; cyanocycloalkyl; aryloxyalkyl; arylalkoxy; cycloalkenyl; cycloalkenylalkyl; cycloalkenyl fused with benzene; dialkylaminoalkyl; hydroxyalkyl; alkylcarbonylalkyl; acylaminoalkyl; aminocarbonylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl; alkylcarbonyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen;
Ar represents an aryl optionally fused with a cycloalkyl or an heterocycle and/or Ar being optionally substituted with one or more alkyl; cyano; halogeno; alkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; alkylsulfanyl; alkylsulfonyl; polyhalogenoalkylsulfanyl; heteroaryl; aryloxy; alkoxy-carbonylamino; acyl; aminocarbonyl; alkylsulfonylamino; polyhalogenoalkyl; hydroxyl; hydroxyalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
According to a further aspect, the compounds of the invention are those of formula (1c):

R is chosen from alkyl; cyanoalkyl; monohalogenocyanoalkyl; polyhalogenocyanoalkyl; hydroxyalkyl; monohalogenoalkyl; polyhalogenoalkyl; cycloalkyl; monhalogenocycloalkyl; polyhalogenocycloalkyl; cyanocycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; monohalogeno-alkoxyalkyl; polyhalogenoalkoxyalkyl; alkoxyalkoxyalkyl; monohalogeno-alkoxyalkoxyalkyl; polyhalogenoalkoxyalkoxyalkyl; alkylcarbonyl; aryl; mono- or polyhalogenoaryl aryloxy; aryloxyalkyl; mono- or polyhalogenoaryloxyalkyl; arylalkoxy; alkenyl; cycloalkenyl; cycloalkenylalkyl; benzofusedcyclalkenyl; alkynyl; amino; alkylamino; dialkylamino; dialkylaminoalkyl; monohalogenoalkylamino; monohalogenodialkylamino; halodialkylaminoalkyl; polyhalogenoalkylamino; polyhalogenodialkylamino; polyhalogenodialkylaminoalkyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl aminocarbonylalkyl; alkylsulfanylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl
n is an integer from 1 to 3;
m is an integer from 0 to 4;
Ar is chosen from an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably, in formula (1c)
R is chosen from alkyl; cyanoalkyl; alkoxy; alkoxyalkyl; aryl; amino; alkoxy(alkyl)amino;
n is 1;
Ar is chosen from aryl optionally fused with a cycloalkyl or an heterocycle; and/or optionally substituted with one or more alkyl; cyano; halogeno; alkoxy; polyhalogenoalkoxy; alkylsulfonyl; polyhalogenoalkylsulfanyl; aralkyl; aryloxy; acyl; polyhalogenoalkyl; hydroxyalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
According to a still further aspect, the compounds of the invention are those of formula (2a):

with
R chosen from cyanoalkyl; monohalogenocyanoalkyl; polyhalogenocyanoalkyl; hydroxyalkyl; monohalogenoalkyl; polyhalogenoalkyl monhalogenocycloalkyl polyhalogenocycloalkyl cyanocycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl monohalogeno-alkoxyalkyl; polyhalogenoalkoxyalkyl alkoxyalkoxyalkyl monohalogeno-alkoxyalkoxyalkyl polyhalogenoalkoxyalkoxyalkyl; alkylcarbonyl; aryloxy; aryloxyalkyl; mono- or polyhalogenoaryloxyalkyl; arylalkoxy; alkenyl; cycloalkenyl; cycloalkenylalkyl benzofusedcyclalkenyl; alkynyl, amino; alkylamino; dialkylamino; dialkylaminoalkyl monohalogenoalkylamino; monohalogenodialkylamino; halodialkylaminoalkyl polyhalogenoalkylamino; polyhalogenodialkylamino; polyhalogenodialkylaminoalkyl
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl; aminocarbonylalkyl; alkylsulfanylalkyl alkylsulfinylalkyl; alkylsulfonylalkyl
m being an integer from 0 to 4;
Ar representing an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably in formula (2a):
R is chosen from cyanoalkyl; polyhalogenoalkyl; alkoxyalkyl; cycloalkenyl
Ar is chosen from an aryl optionally substituted with one or more alkyl; cyano; halogeno; polyhalogenoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
According to a still further aspect, the compounds of the invention are those of formula (2c):

R is chosen from alkyl; cyanoalkyl; monohalogenocyanoalkyl polyhalogenocyanoalkyl; hydroxyalkyl; monohalogenoalkyl; polyhalogenoalkyl; cycloalkyl; monhalogenocycloalkyl; polyhalogenocycloalkyl; cyanocycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; monohalogeno-alkoxyalkyl polyhalogenoalkoxyalkyl; alkoxyalkoxyalkyl monohalogeno-alkoxyalkoxyalkyl polyhalogenoalkoxyalkoxyalkyl; alkylcarbonyl; aryl; mono- or polyhalogenoaryl; aryloxy; aryloxyalkyl; mono- or polyhalogenoaryloxyalkyl; arylalkoxy; alkenyl; cycloalkenyl; cycloalkenylalkyl; benzofusedcyclalkenyl; alkynyl, amino; alkylamino; dialkylamino; dialkylaminoalkyl; monohalogenoalkylamino; monohalogenodialkylamino; halodialkylaminoalkyl; polyhalogenoalkylamino; polyhalogenodialkylamino; polyhalogenodialkylaminoalkyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl aminocarbonylalkyl; alkylsulfanylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl
n is an integer from 1 to 3;
m is an integer from 0 to 4;
Ar is chosen from an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably, in formula (2c):
R is chosen from alkyl
n is 1;
Ar represents an aryl optionally fused with a cycloalkyl and/or optionally substituted with one or more alkyl; cyano; halogeno; polyhalogenoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
According to a still further aspect, the compounds of the invention are those of formula (3c):

R is chosen from alkyl cyanoalkyl monohalogenocyanoalkyl; polyhalogenocyanoalkyl; hydroxyalkyl; monohalogenoalkyl; polyhalogenoalkyl; cycloalkyl; monhalogenocycloalkyl; polyhalogenocycloalkyl; cyanocycloalkyl; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; monohalogeno-alkoxyalkyl polyhalogenoalkoxyalkyl; alkoxyalkoxyalkyl; monohalogeno-alkoxyalkoxyalkyl polyhalogenoalkoxyalkoxyalkyl; alkylcarbonyl aryl; mono- or polyhalogenoaryl aryloxy; aryloxyalkyl; mono- or polyhalogenoaryloxyalkyl; arylalkoxy; alkenyl; cycloalkenyl; cycloalkenylalkyl; benzofusedcyclalkenyl; alkynyl, amino; alkylamino; dialkylamino; dialkylaminoalkyl; monohalogenoalkylamino; monohalogenodialkylamino; halodialkylaminoalkyl; polyhalogenoalkylamino; polyhalogenodialkylamino; polyhalogenodialkylaminoalkyl;
where
is a non aromatic heterocycle optionally fused with aryl or optionally substituted with one or more acyl, alkyl or halogen; arylaminoalkyl; alkoxyalkylamino; alkoxy(alkyl)amino; cyanoalkylamino; alkylcarbonylalkyl; acylaminoalkyl; aminocarbonylalkyl; alkylsulfanylalkyl; alkylsulfinylalkyl; alkylsulfonylalkyl
n is an integer from 1 to 3;
m is an integer from 0 to 4;
Ar is chosen from an aryl; an heteroaryl or an aryl fused with a cycloalkyl or an heterocycle; Ar being optionally substituted with one or more alkyl; alkenyl; alkynyl; cyano; halogeno; alkoxy; monohalogenoalkoxy; polyhalogenoalkoxy; alkoxyalkyl; dialkylamino; non aromatic heterocyclyl attached by a nitrogen; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; monohalogenoalkylsulfanyl; monohalogenoalkylsulfinyl; monohalogenoalkylsulfonyl; polyhalogenoalkylsulfanyl; polyhalogenoalkylsulfinyl; polyhalogenoalkylsulfonyl; heteroaryl; aryl; aralkyl; aryloxy; alkoxy-carbonylamino; acyl; acylamino; aminocarbonyl; monoalkylaminocarbonyl; dialkylaminocarbonyl; alkylsulfonylamino; monohalogenoalkyl; polyhalogenoalkyl; hydroxyl; hydroxyalkyl; oxoalkyl;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferably, in formula (3c);
R is chosen from alkyl;
n is 1;
Ar is an aryl optionally fused with a cycloalkyl and/or optionally substituted with one or more halogeno;
or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Preferred compounds of formula (1) can be chosen from:    2-cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propane-1,2-dione, hydrochloride,    1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,    N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide,    1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclo-hexylidene)propan-2-one,    1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propan-2-one, hydrochloride,    N-(4-{2-[4-(3-acetylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester, hydrochloride,    1-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    (4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetic acid tert-butyl ester, dihydrochloride,    1-Phenyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethanone, dihydrochloride,    1-(4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butane-1,2-dione, hydrochloride,    3,3-Dimethyl-1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butan-2-one,    N-[2-Oxo-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethyl]acetamide,    3-Oxo-3-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propanenitrile, hydrochloride,    2-Methoxy-1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethanone, hydrochloride,    2-Ethoxy-1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethanone, hydrochloride,    5-Oxo-5-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)pentanenitrile, hydrochloride,    3-(4-{2-[1-(2-Oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)-5-trifluoromethylbenzonitrile, dihydrochloride,    1-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    1-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,    2-Methyl-6-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile, dihydrochloride,    2-(4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetamide, dihydrochloride,    1-(4-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    3-(4-{2-[1-(2-Oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile, dihydrochloride,    (4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetic acid ethyl ester, dihydrochloride,    1-(4-{2-[4-(3,5-Difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    1-(4-{2-[4-(2,3-Dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    1-(4-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,    1-{4-[2-(4-o-Tolylpiperazin-1-yl)-thyl]piperidin-1-yl}propan-2-one, dihydrochloride,    1-(4-{2-[4-(2-Chloro-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    1-(4-{2-[4-(5-Fluoro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride,    1-(3,4-Difluorophenyl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethanone,    1-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,    1-(4-{2-[4-(2,3-Difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,    1-{4-[2-(4-Naphthalen-1-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one,    (4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)carbamic acid benzyl ester,    2,2,2-Trifluoro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    (4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)carbamic acid methyl ester,    Tetrahydrofuran-2-carboxylic acid (4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    2-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2,2-Difluoro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    Cyclopent-1-enecarboxylic acid (4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    2-Hydroxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    3-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    N-(4-{2-[4-(2,4-Difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    N-(4-{2-[4-(2-Cyano-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Ethoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    Cyclopent-3-enecarboxylic acid (4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    Cyclohex-1-enecarboxylic acid (4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexyl)-amide,    N-(4-{2-[4-(2-Cyano-3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    N-(4-{2-[4-(2-Cyano-3-methylphenyl)piperidin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Ethoxy-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclo-hexyl)acetamide,    Tetrahydrofuran-2-carboxylic acid (4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    N-(4-{2-[4-(2-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide,    2-Methoxy-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    2-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]ethyl}cyclohexyl)acetamide,    2-Phenoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    3,3,3-Trifluoro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    4-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    Cyclopent-3-enecarboxylic acid {4-[2-(4-pyridin-2-ylpiperazin-1-yl)ethyl]cyclohexyl}amide,    Cyclohex-1-enecarboxylic acid {4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}amide,    Cyclohex-1-enecarboxylic acid (4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    Cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxypropanamide,    Cyclopent-3-enecarboxylic acid (4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    Cyclohex-1-enecarboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    Cyclopent-1-enecarboxylic acid (4-{2-[4-(2-cyano-3-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)amide,    N-(4-{2-[4-(2-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    Cyclopent-1-enecarboxylic acid (4-{2-[4-(2-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxypropanamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide,    2-Methoxy-2-methyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Methylsulfanyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide,    2-Ethoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide,    2-Ethoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]ethyl}cyclohexyl)acetamide,    4-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]ethyl}cyclohexyl)butanamide,    2-(2-Methoxyethoxy)-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    3,3,3-Trifluoro-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-phenoxyacetamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-oxobutanamide,    2-Cyano-N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2,3-Difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide,    2-Oxo-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,hydrochloride,    2-Oxo-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide, hydrochloride,    2-Dimethylamino-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-isopropoxyacetamide,    4-Methoxy-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}butanamide,    2-Isopropoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Cyano-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-isopropoxyacetamide,    N-(4-{2-[4-(2-Cyano-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-(4-{2-[4-(2-cyano-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}acetamide, hydrochloride,    2-Acetylamino-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    3-Oxo-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    N-{4-[2-(6-Cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]cyclohexyl}-3,3,3-trifluoropropanamide,    2-Cyano-N-(4-{2-[4-(2,6-di-tert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2,3-Difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-(4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-cyano-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Cyano-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide,    2-Cyano-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Ethoxy-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    N-(4-{2-[4-(2-Cyano-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Cyano-N-{4-[2-(4-pyridin-4-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    N-(4-{2-[4-(2,6-Di-tert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    N-(4-{2-[4-(2,6-Di-tert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Ethoxy-N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Methoxy-N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2-Cyano-N-(4-{2-[4-(2-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide,    2-Acetylamino-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    N-(4-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Methoxy-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-(4-{2-[4-(3-fluorophenyl-piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Acetylamino-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-tert-Butoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3-Cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    N-(4-{2-[4-(3-Cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Cyano-N-{4-[2-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]cyclohexyl}acetamide,    N-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    2-Cyano-N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide,    2-Acetylamino-N-(4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2,3-Difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-isopropoxyacetamide, hydrochloride,    2-Cyano-N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-dimethylaminophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    1-Acetylpiperidine-4-carboxylic acid (4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    N-(4-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclo-hexyl)succinamide,    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(3-trifluoromethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3,5-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-isopropoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2-Cyano-N-(4-{2-[4-(3-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2-Cyano-N-(4-{2-[4-(2-methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    3-Diethylamino-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    3-Cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide, hydrochloride,    N-(4-{2-[4-(3-tert-Butylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(3-ethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(5-Chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    4-Cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-(4-{2-[4-(6-trifluoromethylbenzo[b]thiophen-3-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-hydroxyphenyl)piperazin-1-yl]ethyl}cyclo-hexyl)acetamide, hydrochloride,    N-(4-{2-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(2-methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide,    2-Cyano-N-(4-{2-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3-Chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(3-methylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-naphthalen-1-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    N-(4-{2-[4-(3-Chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide,    N-{4-[2-(4-Phenylpiperazin-1-yl)ethyl]cyclohexyl}succinamide,    3,3,3-Trifluoro-N-{4-[2-(4-phenylpiperazin-1-yl)ethyl]cyclohexyl}propanamide,    N-(4-{2-[4-(2-Chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide,    4-Oxopentanoic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    2-Cyano-N-(4-{2-[4-(2-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Chloro-5-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(2-methylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-methoxy-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(5-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(5-tert-Butyl-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(5-methoxy-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(3,5-Bis-trifluoromethylphenyl)piperidin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    5-Oxohexanoic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    4-Cyano-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide, hydrochloride,    4-Cyano-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    20-N-(4-{2-[4-(3-Chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    4-Cyano-N-(4-{2-[4-(3-trifluoromethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    4-Cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-(4-{2-[4-(2-cyano-3-fluorophenyl-piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Cyano-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    4-Cyano-N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-2-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-indan-5-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide,    3-Cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    N-(4-{2-[4-(3-Chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-(4-{2-[4-(3-Benzylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    [3-(4-{2-[4-(2-Cyanoacetylamino)cyclohexyl]ethyl}piperazin-1-yl)phenyl]carbamic acid ethyl ester,    2-Cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)piperidin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-o-tolylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    2-Cyano-N-(4-{2-[4-(2,5-dimethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Oxopentanoic acid (4-{2-[4-(3,5-bis-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    4-Dimethylamino-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-(4-Fluorophenoxy)-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(2-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2-Cyano-N-(4-{2-[4-(2,5-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Chloro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(2,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    4-Cyano-N-(4-{2-[4-(2-methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    4-Oxopentanoic acid (4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide,    2-Cyano-N-(4-{2-[4-(3,5-di-tert-butylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    4-Cyano-N-{4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}butanamide,    3,3,3-Trifluoro-N-{4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}propanamide,    4-Cyano-N-(4-{2-[4-(2-methylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-{4-[2-(4-quinolin-8-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    4-Cyano-N-(4-{2-[4-(3-methylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-{4-[2-(4-quinolin-5-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    2-Cyano-N-(4-{2-[4-(3-methanesulfonylaminophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(4-fluoro-phenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-{4-[2-(4-p-tolylpiperazin-1-yl)ethyl]cyclohexyl}acetamide,    2-Cyano-N-(4-{2-[4-(2-ethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide,    2-Cyano-N-(4-{2-[4-(2-phenoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(3-Chloro-2-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(2-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    4-Cyano-N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    N-(4-{2-[4-(3-Ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide,    3-Cyano-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    4-Cyano-N-(4-{2-[4-(6-trifluoromethylbenzo[b]thiophen-3-yl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    4-Cyano-N-(4-{2-[4-(3,5-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    2-Cyano-N-(4-{2-[4-(2,4-diethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    3,3,3-Trifluoro-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide,    5-N-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    N-(4-{2-[4-(3-Chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide,    N-(4-{2-[4-(2-Fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide,    4-Cyano-N-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    4-Cyano-N-{4-[2-(4-quinolin-8-ylpiperazin-1-yl)ethyl]cyclohexyl}butanamide,    4,4,4-Trifluoro-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    3-Cyano-N-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    2-Cyano-N-(4-{2-[4-(2,6-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-hydroxymethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    3-Cyano-N-(4-{2-[4-(3-methylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    2-Cyano-N-(4-{2-[4-(3-methoxymethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3-propylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-(4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    2-Cyano-N-[4-(2-{4-[3-(1-hydroxyethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide,    2-Cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(4-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    N-{4-[2-(4-Biphenyl-3-yl-piperazin-1-yl)ethyl]cyclohexyl}-2-cyanoacetamide,    2-Cyano-N-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    3-Cyano-N-(4-{2-[4-(5-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    4-Cyano-N-(4-{2-[4-(5-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    N-(4-{2-[4-(3-Bromophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide,    2-Cyano-N-[4-(2-{4-[3-(1,1-difluoroethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide,    2-Cyano-2,2-dimethyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Cyano-N-(4-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    3,3,3-Trifluoro-N-(4-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide,    2-Cyano-N-(4-{2-[4-(4-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    4-Cyano-N-(4-{2-[4-(2-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide,    1-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)propan-2-one, hydrochloride,    1-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propan-2-one, hydrochloride,    1-(1,3-Dihydroisoindol-2-yl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)ethanone, hydrochloride,    1-(1,3-Dihydroisoindol-2-yl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)ethanone, hydrochloride 60/40 mixture of isomers,    1-Pyrrolidin-1-yl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)ethanone,    N,N-Dimethyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide,    N,N-Dimethyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    1-Pyrrolidin-1-yl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)ethanone,    N-Methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(2-Methoxyethyl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    N-(2-Methoxyethyl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide,    N-(2-Methoxyethyl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)-N-methylacetamide,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-N-methylacetamide,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)-1-pyrrolidin-1-ylethanone,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-1-pyrrolidin-1-ylethanone,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)-N-(2,2,2-trifluoroethyl)acetamide,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-N-(2,2,2-trifluoroethyl)acetamide,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)-N-propylacetamide,    2-(4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-N-propylacetamide,    N-Cyanomethyl-2-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide,    N-Cyanomethyl-2-(4-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide,    1-(4-fluorophenyl)-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)ethanone, dihydrochloride    1-{4-[2-(4-p-tolylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one    1-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-cyano-N-(4-{2-[4-(3-propylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-(4-{2-[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-[4-(2-{4-[3-(1,1-difluoroethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]butanamide    N-{4-[2-(4-benzo[1,3]dioxol-5-ylpiperazin-1-yl)ethyl]cyclohexyl}-2-cyanoacetamide    2-cyano-N-(4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    3,3,3-trifluoro-N-{4-[2-(4-quinolin-5-ylpiperazin-1-yl)ethyl]cyclohexyl}propanamide    4-cyano-N-{4-[2-(4-quinolin-5-ylpiperazin-1-yl)ethyl]cyclohexyl}butanamide    2-cyano-N-(4-{2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-cyano-cyclopropanecarboxylic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-cyano-N-(4-{2-[4-(3,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3-ethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-ethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    5-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)pentan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-m-tolylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    1-(4-{2-[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-methanesulfinyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3-isopropylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-methanesulfonyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-{4-[2-(4-quinolin-8-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3-trifluoromethylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-methoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile, dihydrochloride    1-(4-{2-[4-(3-propylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-trifluoromethoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-ethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-quinolin-5-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butan-2-one, dihydrochloride    1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(3-difluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(3,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexylbutanamide    N-(4-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(4-chloro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    2-cyano-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    4-cyano-N-(4-{2-[4-(3-trifluoromethylsulfanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(3-difluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-{4-[2-(4-benzo[1,3]dioxol-5-ylpiperazin-1-yl)ethyl]cyclohexyl}-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide, hydrochloride    4-cyano-N-(4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    2-cyano-N-(4-{2-[4-(4-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-3-enecarboxylic acid (4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-cyclopent-2-enyl-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-acetylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    2-cyano-N-(4-{2-[4-(2-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-3-enecarboxylic acid (4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    cyclopent-3-enecarboxylic acid {4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}-cyclopent-1-enecarboxylic acid {4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}amide    N-(4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-(4-fluorophenoxy)acetamide    N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    2-cyclopent-3-enyl-N-(4-{2-[4-(2-fluorophenylpiperazin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(2-chloro-4-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(2-chloro-4-fluoro-5-methylphenylpiperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(5-methoxy-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-chloro-2-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    cyclohex-1-enecarboxylic acid (4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexylamide    4-cyano-N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-phenoxyacetamide    N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    2-cyano-N-(4-{2-[4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    3-cyano-N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    N-(4-{2-[4-(2-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(2-methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    1H-indene-2-carboxylic acid (4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    cyclopent-3-enecarboxylic acid (4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    3,3,3-trifluoro-N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    3-diethylamino-N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    3-cyano-N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    4-cyano-N-(4-{2-[4-(2,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(5-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    N-(4-{2-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(3-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    3-cyano-N-(4-{2-[4-(3-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    2-cyclopent-2-enyl-N-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    2-cyano-N-(4-{2-[4-(2,4-dichloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2,4-dichloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methanesulfonylacetamide    N-(4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methanesulfonylacetamide    N-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methanesulfonylacetamide    4-cyano-N-{4-[2-(4-o-tolylpiperazin-1-yl)ethyl]cyclohexyl}butanamide    4-cyano-N-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(2-chloro-4-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    4-cyano-N-{4-[2-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]cyclohexyl}butanamide    4-cyano-N-(4-{2-[4-(2-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide, hydrochloride    N-(4-{2-[4-(3-chloro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(3-chloro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(2-ethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(2-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,5-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(2,5-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2,2-difluoro-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,3-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    2-cyano-N-(4-{2-[4-(2,3,4-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2,3,4-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    3,3,3-trifluoro-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    1-(4-{2-[4-(3-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-ethoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-cyano-N-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]cyclohexyl}acetamide    4-cyano-N-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]cyclohexyl}butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    4-cyano-2,2-difluoro-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2,2,2-trifluoro-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide            N-{4-[2-(4-biphenyl-3-ylpiperazin-1-yl)ethyl]cyclohexyl}-4-cyanobutanamide            cyclopent-1-enecarboxylic acid (4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-ethoxy-N-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    cyclopent-3-enecarboxylic acid (4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-{4-[2-(4-p-tolylpiperazin-1-yl)ethyl]cyclohexyl}butanamide    4,4,4-trifluoro-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    2-cyano-N-(4-{2-[4-(2,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-ethoxy-N-{4-[2-(4-p-tolylpiperazin-1-yl)ethyl]cyclohexyl}acetamide    cyclopent-1-enecarboxylic acid {4-[2-(4-p-tolylpiperazin-1-yl)ethyl]cyclohexyl}amide    5,6-dihydro-4H-pyran-3-carboxylic acid (4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl amide    3,3,3-trifluoro-N-[4-(2-{4-[3-(1-hydroxyethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]propanamide    2-ethoxy-N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    N-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    1-(4-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-cyano-N-(4-{2-[4-(2-methoxy-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-(4-{2-[4-(2-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    3,3,3-trifluoro-N-{4-[2-(4-p-tolylpiperazin-1-yl)ethyl]cyclohexyl}propanamide    cyclopent-3-enecarboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    1-(4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4,5-dihydrofuran-3-carboxylic acid (4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    4-cyano-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    pyrrolidine-2-carboxylic acid (4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    4-cyano-N-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    4-cyano-N-(4-{2-[4-(5,6,7,8-tetrahydronaphthalen-2-yl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    2-ethoxy-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(4-chloro-phenyl)piperazin-1-yl]ethyl}-cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(2-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-propoxyacetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-cyano-N-(4-{2-[4-(3,4-dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3,4-dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    4-cyano-N-(4-{2-[4-(2-cyano-3-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4,5-dihydrofuran-3-carboxylic acid (4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    cyclopent-1-enecarboxylic acid (4-{2-[4-(5-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(3-oxazol-2-ylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4,5-dihydrofuran-3-carboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(3-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    2-cyano-N-(4-{2-[4-(3-oxazol-2-ylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-ethoxy-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    4,5-dihydrofuran-3-carboxylic acid(4-{2-[4-(3-oxazol-2-ylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    (4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetic acid ethyl ester    cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(3-ethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid {4-[2-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]cyclohexyl}amide    cyclopent-1-enecarboxylic acid (4-{2-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-ethoxy-N-(4-{2-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-[4-(2-{4-[3-(1-hydroxypropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]butanamide    pyrrolidine-2-carboxylic acid (4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide, dihydrochloride    2-methoxy-N-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,3,4-trifluorophenylpiperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    pyrrolidine-2-carboxylic acid (4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(3,4-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(3,4-dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    pyrrolidine-2-carboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide, dihydrochloride    N-(4-{2-[4-(3-chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(3-chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    1-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    cyclopent-1-enecarboxylic acid {4-[2-(4-o-tolylpiperazin-1-yl)ethyl]cyclohexyl}amide    2-ethoxy-N-{4-[2-(4-o-tolylpiperazin-1-ylethyl]cyclohexyl}acetamide    4-cyano-N-{4-[2-(6-cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]cyclohexyl}butanamide    2-cyano-N-{4-[2-(6-cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]cyclohexyl}acetamide    N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    5,6-dihydro-4H-pyran-2-carboxylic acid (4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    5,6-dihydro-4H-pyran-2-carboxylic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-ethoxy-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4,5-dihydrofuran-3-carboxylic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    5,6-dihydro-4H-pyran-2-carboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-cyano-N-[4-(2-{4-[3-(1-hydroxypropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(2,4-difluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)amide    4-methoxy-N-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-{4-[2-(4-indan-5-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    4-cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    cyclopent-1-enecarboxylic acid (4-{2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    2-ethoxy-N-(4-{2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(3,5-difluoro-4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-[4-(2-{4-[3-(1-hydroxy-2-methylpropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide    1-(4-{2-[4-(5,6,7,8-tetrahydro-naphthalen-2-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    N-(4-{2-[4-(3-chloro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(3-chloro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(2-chloro-4-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(2-chloro-4-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(3-chloro-5-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-cyano-N-(4-{2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-benzo[1,3]dioxol-5-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one    cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)amide    2-cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(3-trifluoromethylsulfanylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-[4-(2-{4-[3-(1,1-difluoroethyl)phenyl]piperazin-1-yl}ethyl)piperidin-1-yl]propan-2-one, dihydrochloride    1-(4-{2-[4-(3-difluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-benzo[1,3]dioxol-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    1-(4-{2-[4-(4-chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)-benzonitrile, dihydrochloride    1-(4-{2-[4-(2-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    N-(4-{2-[4-(2-chloro-5-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    1-(4-{2-[4-(2,6-di-tert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(2-chloro-5-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    N-(4-{2-[4-(3-chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    1-(4-{2-[4-(3-acetylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-[3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]propan-1-one    2-methyl-1-[3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]propan-1-one, dihydrochloride    1-[4-(2-{4-[3-(1-Hydroxyethyl)phenyl]piperazin-1-yl}ethyl)piperidin-1-yl]propan-2-one    1-[4-(2-{4-[3-(1-Hydroxypropyl)phenyl]piperazin-1-yl}ethyl)piperidin-1-yl]propan-2-one    1-[4-(2-{4-[3-(1-Hydroxy-2-methylpropyl)phenyl]piperazin-1-yl}ethyl)piperidin-1-yl]propan-2-one    3-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}-3-oxopropanenitrile, hydrochloride    1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propane-1,2-dione, hydrochloride    1-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propane-1,2-dione, hydrochloride    3-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-3-oxopropanenitrile, hydrochloride    2-cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(2-ethoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(2,5-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-{4-[2-(4-indan-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    4-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}-4-oxobutanamide    1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-ylbutane-1,2-dione, hydrochloride    1-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-{4-[2-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]piperidin-1-yl}propan-2-one    2-cyano-N-(4-{2-[4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide, hydrochloride    1-(4-{2-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, dihydrochloride    1-(4-{2-[4-(4-chloro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-biphenyl-3-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    1-(4-{2-[4-(4-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    1-(4-{2-[4-(2,5-dimethoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-indan-4-ylpiperidin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    1-(4-{2-[4-(4-fluorophenyl)piperidin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}pentan-2-one, dihydrochloride    1-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,6-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-chloro-5-methoxyphenylpiperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-Hydroxymethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    3-cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    3-cyano-N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    2-cyano-N-(4-{2-[4-(2-fluoro-4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2-fluoro-4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-butanamide    1-(4-{2-[4-(2-methoxy-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    1-(4-{2-[4-(3-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    4-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}-4-oxo-butanonitrile    1-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    4-methoxy-N-(4-{2-[4-(2,3,4-trifluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4,4,4-trifluorobutanamide    N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-methoxypropanamide    2-cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(2,3,4-trifluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(3-phenoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    1-(4-{2-[4-(3-isopropoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    2-fluoro-5-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile    2-cyano-N-(4-{2-[4-(3-cyano-4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(3-cyano-4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    4-cyano-N-(4-{2-[4-(3-cyano-4-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(2,5-difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    2-cyano-N-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(3-tert-butylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    3-cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-propoxyacetamide, hydrochloride    3,3,3-trifluoro-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)malonamide    1-(4-{2-[4-(3-benzylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(5-ethyl-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(5-ethyl-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-methoxy-N-{4-[2-(4-m-tolylpiperazin-1-yl)ethyl]cyclohexyl}butanamide    1-(4-{2-[4-(3,4-difluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-isopropylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    5-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}-5-oxo-pentanenitrile, hydrochloride    2-ethoxy-1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}ethanone, hydrochloride    3-(1-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile    2-cyano-N-(4-{2-[4-(3-cyanophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(3-cyanophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(3,4-dichloro-2-fluoro-phenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(5-chloro-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-methylsulfanylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    2-cyano-N-(4-{2-[4-(3-cyano-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-cyano-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-fluoro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    2,6-difluoro-3-(4-{2-[1-(2-oxo-propyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile    N-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(3-cyano-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    4-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-4-oxobutanonitrile    1-(4-{2-[4-(3-methoxymethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,3,4,5-tetrafluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3,4,5-trifluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    N-(4-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, trihydrochloride    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    1-(4-{2-[4-(2,4-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,4,5-trichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    4-(4-{2-[4-(3-chloro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-4-oxobutanonitrile, hydrochloride    cyclopent-1-enecarboxylic acid (4-{2-[4-(2-fluoro-5-trifluoromethylphenylpiperazin-1-yl]ethyl}cyclohexyl)amide    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methanesulfonylacetamide    N-(4-{2-[4-(2-fluoro-4-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    2-cyano-N-(4-{2-[4-(2,3,4,5-tetrafluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-cyano-N-(4-{2-[4-(2,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(2,5-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    3-cyano-N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    2-cyano-N-(4-{2-[4-(2,4,5-trichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(3-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3,4-dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    3-cyano-N-(4-{2-[4-(3,4-dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    1-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    4-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)-4-oxobutanonitrile, hydrochloride    2-cyano-N-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-(4-{2-[4-(3-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-fluoro-5-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(2,3,4-trichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(4-fluoro-3-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-cyano-N-(4-{2-[4-(2,3,4-trichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-{4-[2-(4-pentafluorophenylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    5-cyano-pentanoic acid (4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-ylethyl}cyclohexyl)amide    N-(4-{2-[4-(3-chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide    4-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-4-oxobutanonitrile    2-methoxy-N-(4-{2-[4-(2-methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-methoxy-N-(4-{2-[4-(2-methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4,4,4-trifluoro-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    1-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3,5-bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)malonamide    1-(4-{2-[4-(2-ethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3-chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(3,5-bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(3-chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(3-chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide    1-(4-{2-[4-(2,4,5-trifluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    5-cyano-pentanoic acid (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4,4,4-trifluoro-1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}butan-1-one, hydrochloride    3,3,3-trifluoro-1-{4-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-1-one, hydrochloride    2-cyano-N-(4-{2-[4-(2-ethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(2-ethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-{4-[2-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]cyclohexyl}acetamide    4-cyano-N-{4-[2-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]cyclohexyl}butanamide    1-{4-[2-(4-o-tolyl-3,6-dihydro-2H-pyridin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    2-cyano-N-{4-[2-(4-pentafluorophenylpiperazin-1-yl)ethyl]cyclohexyl}acetamide    N-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(4-chloro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    N-(4-{2-[4-(4-chloro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    N-(4-{2-[4-(3-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(2-isobutylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(3-isobutylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(2,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    4-cyano-N-(4-{2-[4-(2,4-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-cyclopropanecarboxylic acid (4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-cyano-N-(4-{2-[4-(2,4,5-trichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    4-cyano-N-(4-{2-[4-(2,3,4-trichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-(4-{2-[4-(2-methylsulfanylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    N-(4-{2-[4-(3-cyanophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(3-cyanophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)-4,4,4-trifluorobutanamide    2-chloro-6-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile, dihydrochloride    1-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethylpiperidin-1-yl)butan-2-one    2-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-N-methoxy-N-methylacetamide    1-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)-3-methylbutan-2-one, hydrochloride    1-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butan-2-one, dihydrochloride    1-(4-{2-[4-(2,3-dimethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)pentan-2-one    3-(4-{2-[4-(4-methoxybutanoylamino)cyclohexyl]ethyl}piperazin-1-yl)benzamide    [3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]carbamic acid ethyl ester    3-oxo-4-(4-{2[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butanenitrile, dihydrochloride    N-(4-{2-[4-(3-acetylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3,3,3-trifluoropropanamide    2-cyano-N-(4-{2-[4-(3-propanoylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-cyano-N-(4-{2-[4-(3-propanoylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-cyano-N-(4-{2-[4-(3-isobutanylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide, dihydrochloride    1-(4-{2-[4-(2-Isopropylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-Methoxy-N-(4-{2-[4-(2,3,4,5-tetrafluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butyramide    4-Cyano-N-(4-{2-[4-(2,3,4,5-tetrafluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)butyramide    2-Chloro-6-fluoro-3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile    1-(4-{2-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(5-Methoxy-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    2-Cyano-N-(4-{2-[4-(2-methyl-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-Cyano-N-(4-{2-[4-(2-methyl-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butyramide    1-(4-{2-[4-(3,5-Di-tert-butylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    2-Cyano-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    1-(4-{2-[4-(4-Methyl-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    2-Methyl-5-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)benzonitrile    1-(4-{2-[4-(3-Methoxy-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2-Fluoro-4-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(3,5-Difluoro-4-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2,3-Dichlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(2,3-Dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-{4-[2-(4-Benzothiazol-5-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one    1-(4-{2-[4-(4,5-Dichloro-2-fluorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    1-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one,            or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.        
More particularly:    1-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    4-Methoxy-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    N-(4-{2-[4-(3-Cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(3-Cyano-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-ethoxyacetamide    2-Cyano-N-(4-{2-[4-(3,5-dimethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-Cyano-N-(4-{2-[4-(3-ethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-Cyano-N-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-Cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    5-N-(4-{2-[4-(3-Chloro-5-fluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    4-Cyano-N-(4-{2-[4-(2-fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    N-(4-{2-[4-(5-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-cyanopropanamide    2-Cyano-N-(4-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-Cyano-N-(4-{2-[4-(4-fluoro-3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    4-Cyano-N-[4-(2-{4-[3-(1,1-difluoroethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]butanamide    1-(4-{2-[4-(3-Propylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    2-Cyano-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    1-{4-[2-(4-Indan-4-ylpiperazin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    2-Cyano-N-(4-{2-[4-(3-difluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-Cyano-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    N-(4-{2-[4-(3-Acetylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    Cyclopent-1-enecarboxylic acid (4-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)amide    4-Cyano-N-(4-{2-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]ethyl}cyclohexyl)butanamide    2-Cyano-N-(4-{2-[4-(3,5-dimethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    3,3,3-Trifluoro-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)propanamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    4-Cyano-N-[4-(2-{4-[3-(1-hydroxypropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]butanamide    N-(4-{2-[4-(3-Chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-cyanobutanamide    2-Cyano-N-[4-(2-{4-[3-(1-hydroxypropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide    N-(4-{2-[4-(3-Chloro-2,4-difluorophenyl)piperazin-1-yl]ethyl}cyclohexyl)succinamide    N-(4-{2-[4-(2-Fluoro-5-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide    1-{4-[2-(4-Indan-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]piperidin-1-yl}propan-2-one, dihydrochloride    1-(4-{2-[4-(2-Fluoro-5-trifluoromethylphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihyrochloride    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4,4,4-trifluorobutanamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-methoxypropanamide    1-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride
or their pharmaceutically acceptable salts, free forms, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
Still more preferably:
    1-(4-{2-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride    1-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-methoxyacetamide    N-(4-{2-[4-(3,5-Bistrifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide    2-Cyano-N-(4-{2-[4-(3-methanesulfonylphenyl)piperazin-1-yl]ethyl}cyclohexyl)acetamide    2-Cyano-N-(4-{2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethyl}cyclohexyl)acetamide    2-Cyano-N-[4-(2-{4-[3-(1-hydroxypropyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4,4,4-trifluorobutanamide    N-(4-{2-[4-(3-Cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-3-methoxypropanamide    1-(4-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one, dihydrochloride
or their pharmaceutically acceptable salts, free forms, hydrates, or hydrated salts, or the polymorphic, cristalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers.
As used hereabove or hereafter:
“Acyl” means an H—CO— or alkyl-CO— group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
“Acylamino” is an acyl-NH— group wherein acyl is as defined herein.
“Acylaminoalkyl” means an acyl-NH-alkyl wherein acyl and alkyl are as defined herein.
“Alcanediyl” means a —(CH2)q— wherein q is an integer from 3 to 6, preferably from 3 to 5.
“Alkenyl” means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having 2 to 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably about 2 to 4 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl.
“Alkoxy” means an alkyl-O— group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
“Alkoxyalkyl” means an alkyl-O-alkyl- group wherein the alkyl groups are independent as herein described. Exemplary alkoxy groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.
“Alkoxyalkoxyalkyl” means an alkyl-O-alkyl-O-alkyl- group wherein the alkyl groups independently are as defined above.
“Alkoxyalkylamino” means an alkyl-O-alkyl-NH— wherein alkyl is as defined herein.
“Alkoxy(alkyl)amino” means an alkyl-O—N(alkyl)- wherein alkyl is as defined herein.
“Alkoxycarbonylamino” means an alkyl-O—CO—NH— wherein alkyl is as defined herein.
“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched having 1 to 20 carbon atoms in the chain. Preferred alkyl groups have 1 to 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl.
Alkyl groups may be substituted with a cyano group (“Cyanoalkyl”), a hydroxyl group (“Hydroxyalkyl”), a halogeno group (“Monohalogenoalkyl”) or more (“Polyhalogenoalkyl”).
“Alkylamino” means an alkyl-NH— group wherein the alkyl group is as herein described.
“Alkylcarbonylalkyl” means an alkyl-CO-alkyl- wherein alkyl are independently as defined herein.
“Alkylsulfanyl” means an alkyl-S— group wherein the alkyl group is as herein described.
“Alkylsulfanylalkyl” means an alkyl-S-alkyl- group wherein the alkyl groups are independently as herein described.
“Alkylsulfinyl” means an alkyl-SO— group wherein the alkyl group is as defined herein. Preferred groups are those wherein the alkyl group is lower alkyl.
“Alkylsulfinylalkyl” means an alkyl-SO-alkyl- group wherein the alkyl groups are independently as defined above. Preferred groups are those wherein the alkyl group is lower alkyl.
“Alkylsulfonyl” means an alkyl-SO2— group wherein the alkyl group is as defined herein. Preferred groups are those wherein the alkyl group is lower alkyl.
“Alkylsulfonylalkyl” means an alkyl-SO2-alkyl- group wherein the alkyl groups are independently as defined herein. Preferred groups are those wherein the alkyl group is lower alkyl.
“Alkylsulfonylamino” means an alkyl-SO2—NH— wherein alkyl is as defined herein.
“Alkynyl” means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.
“Aminocarbonylalkyl” means an NH2—CO-alkyl- wherein alkyl is as defined herein.
“Aralkyl” means an aryl-alkyl- group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthylmethyl.
“Aryl” means an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl.
“Arylaminoalkyl” means an aryl-NH-alkyl- wherein aryl and alkyl are as defined herein.
“Arylalkoxy” means an aryl-alkyl-O— group wherein the aryl or alkyl groups are as herein described.
“Aryloxy” means an aryl-O— group wherein the aryl group is as defined herein. Exemplary groups include phenoxy and 2-naphthyloxy.
“Aryloxyalkyl” means an aryl-O-alkyl- group wherein the aryl or alkyl groups are as herein described. An exemplary aryloxyalkyl groups is phenoxypropyl.
“Cycloalkenyl” means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl. An exemplary multicyclic cycloalkenyl is norbornenyl.
“Cycloalkyl” means a non-aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 5 to 10 carbon atoms. Preferred ring sizes of rings of the ring system include 5 to 6 ring atoms. Exemplary monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary multicyclic cycloalkyl include 1-decalin, norbornyl, adamant-(1- or 2-)yl.
“Dialkylamino” means an (alkyl)2N— group wherein the alkyl groups are independently as herein described.
“Dialkylaminoalkyl” means an (alkyl)2N-alkyl- group wherein the alkyl groups are independently as herein described.
“Halogeno” refers to fluorine, chlorine, bromine or iodine atom; preferably fluorine and chlorine atom.
As used herein, the term “Heteroaryl” or aromatic heterocycles refers to a 5 to 14, preferably 5 to 10 membered aromatic hetero, mono-, bi- or multicyclic ring. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazoyl, isoquinolyl, benzothienyl, isobenzofuryl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, as well as the fused systems resulting from the condensation with a phenyl group.
As used herein, the terms “Heterocycle” or “Heterocyclic” refer to a saturated, partially unsaturated or unsaturated, non aromatic stable 3 to 14, preferably 5 to 10 membered mono, bi or multicyclic rings wherein at least one member of the ring is a hetero atom. Typically, heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms. Preferable heteroatoms are oxygen, nitrogen and sulfur.    Suitable heterocycles are also disclosed in The Handbook of Chemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, pages 2-25 to 2-26, the disclosure of which is hereby incorporated by reference.
Preferred non aromatic heterocyclic include, but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxiranyl, tetrahydrofuranyl, dioxolanyl, dioxanyl, piperidyl, piperazinyl, morpholinyl, pyranyl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydro-pyridyl, dihydropyridyl, tetrahydropyrimidinyl, dihydrothiopyranyl, azepanyl, as well as the fused systems resulting from the condensation with a phenyl group.
“Oxoalkyl” means an alkyl where a CH2 is replaced by a CO wherein alkyl is as defined herein.
“Polymethylenedioxy” means a —O—(CH2)p—O— wherein p is an intenger from 1 to 4.
“Fused arylheterocyclyl” means a fused aryl and heterocyclyl as defined herein. Preferred fused arylheterocyclyls are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. A fused arylheterocyclyl as a variable may be bonded through any atom of the ring system thereof capable of such. The designation of the aza, oxa or thia as a prefix before heterocyclyl portion of the fused arylheterocyclyl define that at least a nitrogen, oxygen or sulphur atom is present respectively as a ring atom. The nitrogen atom of a fused arylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary preferred fused arylheterocyclyl ring systems include indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindol-2-yl, 2,3-dihydrobenz[f]isoindol-2-yl, 1,2,3,4-tetrahydrobenz[g]isoquinolin-2-yl.
“Fused arylcycloalkyl” means a fused aryl and cycloalkyl as defined herein. Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkyl as a variable may be bonded through any atom of the ring system thereof capable of such. Exemplary fused arylcycloalkyl includes 1,2,3,4-tetrahydronaphthyl.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propanoic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucuronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, and the like. Further addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. Hydrochloride and oxalate salts are preferred.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The compounds of the general formula (I) having geometrical and stereomers are also a part of the invention.
According to a further object, the present invention is also concerned with the process of preparation of the compounds of formula (I).
The compounds and process of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereon as appreciated by the skilled artisan. The appropriate modifications and substitutions will be readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art.
In particular, such methods can be found in R. C. Larock, Comprehensive Organic Transformations, VCH publishers, 1989.
It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
Compounds of the present invention may be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available, or readily synthesized by well-known techniques by one of ordinary skill in the arts. All substituents, unless otherwise indicated, are as previously defined.
In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.
Some reactions may be carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; alkyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide.
Usually, reactions are carried out in a suitable solvent. A variety of solvents may be used, provided that it has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include: hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, methylcyclohexane, toluene and xylene; amides, such as N,N-dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether and tetrahydrofuran.
The reactions can take place over a wide range of temperatures. In general, we find it convenient to carry out the reaction at a temperature of from 0° C. to 150° C. (more preferably from about room temperature to 100° C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 3 hours to 20 hours will usually suffice.
The compound thus prepared may be recovered from the reaction mixture by conventional means. For example, the compounds may be recovered by distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the residue into water followed by extraction with a waterimmiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, if desired, be further purified by various well-known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
The process of preparation of a compound of formula (I) of the invention is another object of the present invention.
According to a first aspect, compounds of the invention of the formula (I) can be obtained from corresponding compounds of formula (II)

wherein R′, R′1 and R′2 represent respectively R, R1 and R2 or a precursor group of respectively R, R1 and R2.
More precisely, compounds of formula (I) can be obtained by a method comprising the steps of:
a) converting the compound of formula (II) into a compound of formula (I); and optionally
b) isolating the obtained compound of formula (I).
According to the present invention, “precursor group” of a functional group refers to any group which can, by one or more reactions, lead to the desired function, by means of one or more suitable reagents. Those reactions include the deprotections of functional groups, as well as usual addition, substitution, reduction, oxidation or functionalization reaction.
Preferably, a compound of formula (I) in which Ar in NR1R2 is substituted with an acyl group can be prepared from a corresponding compound of formula (II) in which Ar in NR1R2 is substituted with an hydroxylated chain. This reaction can be performed by Swern or Swern Moffatt oxidation as well as action of metallic oxide such as chromium or manganese oxides.
Preferably, a compound of formula (I) in which Z is e) can be prepared from a corresponding compound of formula (II) in which Z is f by reduction. This reaction can be performed with hydrogen and a transition metal catalyst such as palladium or nickel.
Preferably, a compound of formula (I) in which R is alkyl can be prepared from a corresponding compound of formula in which R is alkoxy by hydrolyzing this ester into the corresponding acid (R═OH), converting the acid into Weinreb's amide (R═N(Me)OMe) and finally reacting with a grignard's reagent.
Preferably, a compound of formula (I) in which Z is e) or f and R is an amine can be prepared from the corresponding acid (R═OH) by a peptidic coupling reaction. This reaction is performed using reagents such as a carbodiimide, carbonyldiimidazole or a chloroformate in the presence of catalysts such as DMAP, HOBt in an inert solvent such as dichloromethane, N,N-dimethylformamide, tetrahydrofuran or ethyl acetate at a temperature comprised between 0° C. and 40° C.
Compounds of the invention of the formula (II) in which Z is
can be prepared by coupling compounds of formula (III) with acid or acid derivatives R′COX or R′COCOX
in which R′ and NR′1R′2 are as defined in general formula (II) and Z is chosen from the group selected within:

More precisely, when the reaction can be a peptidic coupling with R′COOH or R′COCOOH and is performed using reagents such as a carbodiimide, carbonyldiimidazole or a chloroformate in the presence of catalysts such as DMAP, HOBt in an inert solvent such as dichloromethane, N,N-dimethylformamide, tetrahydrofuran or ethyl acetate at a temperature comprised between 0° C. and 40° C.
Compound R′COX or R′COCOX can also be an activated form of a carboxylate such as an acid chloride (X═Cl), an imidazolide (X=imidazol-1-yl), an hydroxysuccinimidoyl (X═OSu), a paranitrophenyl ester (X=4-nitrophenoxy), a mixed anhydride or a symmetric anhydride. The reaction is performed in an inert solvent such as dichloromethane, N,N-dimethylformamide, tetrahydrofuran or ethyl acetate at a temperature comprised between 0° C. and 40° C., optionally in the presence of a catalyst such as DMAP or HOBt and a base such as triethylamine or a carbonate.
Compounds of formula (III) can be obtained by deprotection of compounds of formula (IV)
where P represent a nitrogen protecting group such as benzyloxycarbonyl or tertbutoxycarbonyl.
When P is benzyloxycarbonyl, deprotection can be performed using dihydrogen, cyclohexene or a formate in the presence of a catalyst such as palladium on charcoal in an alcohol such as methanol or ethanol at a temperature comprised between room temperature and 80° C., or with aluminum trichloride in the presence of anisole.
When P is tert-butoxycarbonyl, deprotection can be performed using trimethylsilyliodide, or a Brönsted acid such as trifluoroacetic acid or hydrochloric acid, or a Lewis acid such as tin tetrachloride in a suitable solvent at a temperature comprised between 0 and 40° C.
Compounds of formula (IV) can be prepared by nucleophilic substitution of compounds of formula (V)
where L represents a leaving group such as an halogen or a sulfonate (mesylate or arylsulfonate).
This substitution can be performed by mixing compound (V) and the amine HNR′1R′2 in a suitable solvent such as acetonitrile, acetone, N,N-dimethylformamide, dichloromethane or an alcohol, in the presence of a base such as a carbonate, a bicarbonate or a tertiary amine, at a temperature comprised between room temperature and the refluxing temperature.
Compounds of formula (V) can be prepared from the corresponding alcohol of formula (VI)

This reaction can be performed using thionyl chloride with or without imidazole, or a phosphine and tetrahalomethane or hexahaloethane, or a sulfonyl chloride or anhydride in a suitable solvent at a temperature comprised between 0° and 40° C.
Alternatively, compounds of formula (II) in which Z represents

can be prepared from compounds of formula (VII) by reductive amination

This reaction can be performed with an ammonium such as ammonium acetate or chloride in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride in an alcohol such as methanol or ethanol and optionally water at a temperature comprised between −20° C. and reflux.
Compounds of formula (VII) can be prepared by deprotecting spiroketal of formula (VII)

This deprotection can be performed with an acid such as hydrochloric acid, sulfuric acid or a sulfonic acid in an alcohol such as methanol or ethanol and water at a temperature comprised between room temperature and reflux.
Compounds of formula (VIII) can be prepared from the corresponding mesylate

This substitution can be performed by mixing the mesylate and the amine HNR′1R′2 in a suitable solvent such as acetonitrile, acetone, N,N-dimethylformamide, dichloromethane or an alcohol, in the presence of a base such as a carbonate, a bicarbonate or a tertiary amine, at a temperature comprised between room temperature and the refluxing temperature.
Compounds of formula (VIII) can also be prepared by reduction of amides of formula (IX)

This reduction can be performed with lithium aluminum hydride in an ether such as diethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether or tetrahydrofuran at a temperature comprised between 0° C. and reflux.
Compounds of formula (VIII) can also be prepared from the corresponding further mesylate of formula:

This substitution can be performed by mixing the mesylate and the amine HNR′1R′2 in a suitable solvent such as acetonitrile, acetone, N,N-dimethylformamide, dichloromethane or an alcohol, in the presence of a base such as a carbonate, a bicarbonate or a tertiary amine, at a temperature comprised between room temperature and the refluxing temperature.
This further mesylate can be prepared from the corresponding 4-(2-hydroxyethyl)cyclohexanone

This reaction can be performed by reacting 4-(2-hydroxyethyl)cyclohexanone with methanesulfonyl chloride, methanesulfonyl fluoride or methanesulfonic anhydride in the presence of an organic or inorganic base such as pyridine, triethylamine, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,8-diazabicyclo[5,4,0]undec-7-ene, a carbonate or a bicarbonate in an inert solvent such as dichloromethane, dichloroethane, an aromatic solvent, an ether or a mixture thereof, at a temperature comprised between −20° C. and the refluxing temperature.
4-(2-hydroxyethyl)cyclohexanone is a known intermediate in various industrial fields such as pharmaceutical synthesis and liquid crystals elaboration, it can be prepared from 4-(2-hydroxyethyl)cyclohexanol by selective oxydation

This oxydation can be performed with an oxydant able to convert a secondary alcohol into a ketone in the presence of a primary alcohol. Such oxydant can be a hypochlorite salt such as sodium or calcium hypochlorite in a suitable solvent such as a carboxylic acid, water, or a mixture thereof.
Alternatively, non selective oxydant can be used with prior protection of the primary alcohol before the oxydation step.
4-(2-hydroxyethyl)cyclohexanol is a known intermediate in various industrial fields such as pharmaceutical synthesis and liquid crystals elaboration, it can be prepared by reduction of 4-(2-hydroxyethyl)phenol

This reduction can be performed with hydrogen or a hydrogen donor (such as cyclohexene, formic acid, formic acid triethylamine eutectic mixture) in the presence of a metal catalyst (such as palladium, platinum, nickel or ruthenium supported on charcoal, silica or alumina) eventually in the presence of an additive (such as borax, sodium acetate, potassium acetate, lithium acetate, sodium hydroxyde, lithium hydroxyde, potassium carbonate, sodium carbonate, potassium hydrogenocarbonate or sodium hydrogenocarbonate in a suitable solvent such as an alcohol (methanol, ethanol, isopropanol), water, a carboxylic acid (acetic acid, propanoic acid), an ether (diethyl ether, methyl tert-butyl ether, tetrahydrofurane, dioxane, cyclopentyl methyl ether), an aromatic solvent (toluene, xylene) or a mixture thereof
Amides of formula (IX) can be prepared by condensing amine HNR′1R′2 with (1,4-dioxaspiro[4.5]dec-8-yl)acetic acid.

This reaction can be performed using reagents such as a carbodiimide, carbonyldiimidazole or a chloroformate in the presence of catalysts such as DMAP, HOBt in an inert solvent such as dichloromethane, N,N-dimethylformamide, tetrahydrofuran or ethyl acetate at a temperature comprised between 0° C. and 40° C.
According to a third aspect, compounds of the invention of the formula (II) in which Z is

can be prepared by alkylating compounds of formula (III) with haloketones R′CO(CH2)nBr or R′CO(CH2)nCl

in which NR′1R′2 is as defined in formula (II) and Z is

This alkylation can be performed by reacting the amine of formula (III) and the haloketone R′CO(CH2)nBr or R′CO(CH2)nCl in the presence of base such as a carbonate or a bicarbonate in an inert solvent such as acetonitrile or a ketone (acetone, methylisobutylketone, methylethylketone) or an alcohol (methanol, ethanol or isopropanol) at a temperature comprised between room temperature and reflux.
According to a fourth aspect, compounds of the invention of the formula (II) in which Z is
can be prepared by condensing a compound of formula (VII) with a (triphenyl-λ5-phosphanylidene)acetic acid ester by refluxing in an inert solvent like toluene or a (diethoxyphosphoryl)acetic acid ester in the presence of a base such as sodium hydroxyde or sodium hydride at a temperature comprised between 0° C. and 40° C. in a solvent such as an ether (tetrahydrofuran, methyl-tert-butyl ether, methyl cyclopentyl ether).

These general methods can be summarised in the following scheme:

According to a further object, the present invention is also concerned with pharmaceutical compositions comprising a compound of formula (I) together with a pharmaceutically acceptable excipient or carrier.
According to another object, the present invention also relates to the use of compounds of general formula (I) for the preparation of pharmaceutical compositions intended to prevent and/or treat a neuropsychiatric illness or any illness involving the dopamine D3 receptor. Said neuropsychiatric illnesses are preferably selected from Parkinson's disease, schizophrenia, dementia, psychosis or psychotic states, depression, mania, anxiety, dyskinesias, equilibration disorders, Gilles de la Tourette's disease.
According to the invention, said prevention and/or treatment of Parkinson's disease is preferably an adjunct therapy for Parkinson's disease.
Other illnesses include substance dependency, sexual disorders, motor disorders, cardiovascular disorders, hormonal disorders, renal insufficiency or diabetes.
According to the invention, substance dependency is taken to mean any state associated withdrawal, abstinence and/or detoxification of an individual dependent on any agent, in particular therapeutically active agents, such as opioids, and/or drugs such as cocaine, heroin, or alternatively alcohol and/or nicotine.
According to the invention, sexual disorders are in particular taken to mean impotence, in particular male impotence.
According to the invention, motor disorders are in particular taken to mean essential or iatrogenic dyskinesia, and/or essential or iatrogenic tremor.
According to the invention, cardiovascular disorders comprise hypertension, cardiac failure.
According to the invention, hormonal disorders comprise menopausal disorders or growth disorders.
According to another object, the present invention also relates to the above-mentioned therapeutic treatment methods comprising the administration of a compound according to the invention together with a pharmaceutically acceptable carrier or excipient to a patient in the need thereof.
According to a further object, the present invention also relates to combinations comprising a compound of the invention and one or more further active ingredient(s).
In particular, for treating neuropsychiatric disorders, compounds of the invention may be advantageously administered with one or more other neuropsychiatric agent(s) such as anxyolytic, antipsychotic, antidepressant, precognitive or antidementia agents.
Also, for treating cardiovascular or metabolic disorders, compounds of the invention may be advantageously administered with one or more antihypertensive, cardiotonic or antidiabetic agent(s).
The identification of those subjects who are in need of treatment of herein-described diseases and conditions is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination, genetic tests and medical/family history, those subjects who are in need of such treatment.
A therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The amount of a compound of formula (I), which is required to achieve the desired biological effect, will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g. hydrophobicity) of the compounds employed, the potency of the compounds, the type of disease, the diseased state of the patient and the route of administration.
“Pharmaceutically” or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
As used herein, “pharmaceutically acceptable carrier” includes any diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
In the context of the invention, the term “treating” or “treatment”, as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
“Therapeutically effective amount” means an amount of a compound/medicament according to the present invention effective in producing the desired therapeutic effect.
According to the invention, the term “patient”, or “patient in need thereof”, is intended for a human or non-human mammal affected or likely to be affected with a neuropsychological disorder. Preferably, the patient is a human.
In general terms, the compounds of this invention may be provided in an aqueous physiological buffer solution containing 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from 1 μg/kg to 0.1 g/kg of body weight per day; a preferred dose range is from 0.01 mg/kg to 10 mg/kg of body weight per day. A preferred daily dose for adult humans includes 5, 50, 100 and 200 mg, and an equivalent dose in a human child. The preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
The compounds of the present invention are capable of being administered in unit dose forms, wherein the term “unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter. As such, typical daily dose ranges are from 0.01 to 10 mg/kg of body weight. By way of general guidance, unit doses for humans range from 0.1 mg to 1000 mg per day. Preferably the unit dose range is from 1 to 500 mg administered one to four times a day, and even more preferably from 10 mg to 300 mg, two times a day. Compounds provided herein can be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients. Such compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, for example, topically or via trans-dermal patches.
The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, A. R., Ed.; Lippincoft Williams & Wilkins: Philadelphia, Pa., 2000. Pharmaceutically compatible binding agents and/or adjuvant materials can be included as part of the composition. Oral compositions will generally include an inert diluent carrier or an edible carrier.
The tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings. In addition, the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal.
Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated for oral or parenteral administration, or more preferably those in which a compound of the present invention is formulated as a tablet. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. It is also an aspect of the present disclosure that a compound of the present invention may be incorporated into a food product or a liquid.
Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, buffered media, and saline. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
Alternative modes of administration include formulations for inhalation, which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for buccal administration include, for example, lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa buffer, and may include a salicylate. Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, or their combinations. Formulations suitable for transdermal administration can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
The following examples illustrate the invention, but do not limit it. The starting products used are products which are known or prepared using known methods.
Unless otherwise stated, percentages are weight percentages.